U.S. patent application number 14/099635 was filed with the patent office on 2014-11-06 for buffered compositions for dialysis.
This patent application is currently assigned to Advanced Renal Technologies. The applicant listed for this patent is Advanced Renal Technologies. Invention is credited to Robin Callan, James J. Cole, Walter A. Van Schalkwijk.
Application Number | 20140328948 14/099635 |
Document ID | / |
Family ID | 33564176 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140328948 |
Kind Code |
A1 |
Callan; Robin ; et
al. |
November 6, 2014 |
BUFFERED COMPOSITIONS FOR DIALYSIS
Abstract
Acid concentrates, and dialysate compositions prepared
therefrom, contain citric acid and an effective amount of a
buffering agent selected from acetate and/or lactate. The buffering
agent allows a physiologically acceptable amount of citrate to
maintain the desired pH of the dialysate.
Inventors: |
Callan; Robin; (Medina,
WA) ; Van Schalkwijk; Walter A.; (Redmond, WA)
; Cole; James J.; (Arlington, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Advanced Renal Technologies |
Bellevue |
WA |
US |
|
|
Assignee: |
Advanced Renal Technologies
Bellevue
WA
|
Family ID: |
33564176 |
Appl. No.: |
14/099635 |
Filed: |
December 6, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13789391 |
Mar 7, 2013 |
|
|
|
14099635 |
|
|
|
|
12684546 |
Jan 8, 2010 |
|
|
|
13789391 |
|
|
|
|
10606150 |
Jun 24, 2003 |
7670491 |
|
|
12684546 |
|
|
|
|
09421622 |
Oct 19, 1999 |
6610206 |
|
|
10606150 |
|
|
|
|
60105049 |
Oct 20, 1998 |
|
|
|
Current U.S.
Class: |
424/678 |
Current CPC
Class: |
A61K 33/26 20130101;
A61K 31/19 20130101; A61M 1/1672 20140204; A61K 45/06 20130101;
A61M 1/1666 20140204; A61P 7/08 20180101; A61M 1/1654 20130101;
A61K 33/14 20130101; A61K 31/7004 20130101; A61K 33/26 20130101;
A61K 33/00 20130101; A61K 31/194 20130101; A61K 31/19 20130101;
A61K 2300/00 20130101; A61P 13/12 20180101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61M 1/1656 20130101; A61K 33/14 20130101;
A61M 1/287 20130101 |
Class at
Publication: |
424/678 |
International
Class: |
A61M 1/16 20060101
A61M001/16; A61M 1/28 20060101 A61M001/28; A61K 31/7004 20060101
A61K031/7004; A61K 31/19 20060101 A61K031/19; A61K 31/194 20060101
A61K031/194; A61K 33/14 20060101 A61K033/14 |
Claims
1.-19. (canceled)
20. A buffered dialysate composition comprising treated water;
chloride at a concentration ranging from 40 to 150 mEq/L; citrate
at a concentration ranging from 1.5 to 4.5 mEq/L; a buffering anion
selected from acetate, in the form of an acetate salt, and/or
lactate, in the form of a lactate salt at a concentration ranging
from 0.2 to 0.5 mEq/L; bicarbonate at a concentration ranging from
25 to 45 mEq/L; and at least one physiologically-acceptable cation
selected from hydrogen, sodium at a concentration ranging from 60
to 190 mEq/L, potassium at a concentration of less than 5 mEq/L,
calcium at a concentration of less than 5 mEq/L, and magnesium at a
concentration of less than 2 mEq/L; and glucose at a concentration
of less than 45 g/L, wherein the combined composition meets or
exceeds the AAMI-quality standard set for dialysate.
21. The dialysate composition of claim 20 wherein the water meets
or exceeds the purity requirements established by Association for
the Advancement of Medical Instrumentation (AAMI) for dialysate and
all other components have at least United States Pharmacopeia
(USP)-grade purity.
22. The dialysate composition of claim 20 or 21 wherein the pH is 5
to 8.5 at a temperature of 25.degree. C. to 40.degree. C.
23. The dialysate composition of claim 20 or 21 comprising chloride
at a concentration ranging from 60 to 120 mEq/L; citrate at a
concentration ranging from 2 to 3 mEq/L; acetate, in the form of an
acetate salt, at a concentration ranging from 0.2 to 0.5 mEq/L;
bicarbonate at a concentration ranging from 25 to 45 mEq/L; at
least one physiologically-acceptable cation selected from hydrogen,
sodium at a concentration ranging from 70 to 150 mEq/L, potassium
at a concentration of less than 5 mEq/L, calcium at a concentration
of less than 5 mEq/L, and magnesium at a concentration of less than
2 mEq/L; and glucose in the form of dextrose at a concentration of
less than 8 g/L, where the dialysate composition meets or exceeds
the AAMI-quality standard set for dialysate.
24. A method of forming a buffered dialysate composition comprising
mixing a dialysate precursor composition with an aqueous
bicarbonate-containing solution, the dialysate precursor
composition comprising treated water, chloride, citrate, at least
one buffering anion selected from acetate, in the form of an
acetate salt, and lactate, in the form of a lactate salt, and at
least one physiologically-acceptable cation to provide a dialysate
composition having chloride at a concentration ranging from 60 to
120 mEq/L, citrate at a concentration ranging from 1.5 to 4.5
mEq/L, and at least one buffering anion selected from acetate, in
the form of an acetate salt, and lactate, in the form of a lactate
salt, at a concentration ranging from 0.2 to 0.5 mEq/L; bicarbonate
at a concentration ranging from 25 to 45 mEq/L; and at least one
physiologically-acceptable cation selected from hydrogen, sodium at
a concentration ranging from 60 to 190 mEq/L, potassium at a
concentration of less than 5 mEq/L, calcium at a concentration of
less than 5 mEq/L, and magnesium at a concentration of less than 2
mEq/L; and glucose at a concentration of less than 45 g/L, wherein
the combined composition meets or exceeds the AAMI-quality standard
set for dialysate.
25. The method of claim 24 wherein the dialysate composition has a
final pH from 7.2 to 7.4 at a temperature from 25.degree. C. to
40.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/789,391, filed Mar. 7, 2013 (now pending);
which is a divisional of U.S. patent application Ser. No.
12/684,546, filed Jan. 8, 2010 (now pending); which is a divisional
of U.S. patent application Ser. No. 10/606,150, filed Jun. 24, 2003
(now U.S. Letters Patent No. 7,670,491 issued Mar. 2, 2010); which
is a continuation-in-part of U.S. patent application Ser. No.
09/421,622, filed Oct. 19, 1999 (now U.S. Letters Patent No.
6,610,206, issued Aug. 26, 2003); which application claims the
benefit of U.S. Provisional Patent Application No. 60/105,049,
filed Oct. 20, 1998. These applications are incorporated herein by
reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to therapeutic compositions,
and particularly to dialysate compositions.
[0004] 2. Description of the Related Art
[0005] When functioning correctly, the kidneys help the body
maintain a normal internal environment called homeostasis. Kidneys
help accomplish this normal balance by ridding the body of excess
fluids and metabolic waste products (toxins) as well as maintaining
precise levels of glucose and electrolytes. Kidney failure can be
caused by multiple factors. However, regardless of why a person's
kidneys fail, the failure results in the accumulation of excess
fluid and toxic waste in that person's body. This uremic poisoning
eventually causes death unless the waste material is removed by
some artificial means. Hemodialysis is the most common therapeutic
measure for a person whose kidneys no longer perform their blood
purifying function. Another common type of dialysis is peritoneal
dialysis (PD).
[0006] Dialysate is the fluid utilized in dialysis, where dialysate
serves to `clean` the blood of kidney failure patients. During
hemodialysis, the patient's blood is circulated on one side of a
membrane within a dialyzer (i.e., artificial kidney), while
dialysate flows on the other side of the membrane. Since blood and
dialysate are separated by a semipermeable membrane, movement of
molecules can occur between the blood and dialysate. Although the
membrane pores are too small to permit blood cells and proteins to
leave the blood, the pores allow waste products to be transferred
from the blood to the dialysate.
[0007] Peritoneal dialysis utilizes the patient's peritoneal
membrane as a dialysis membrane. Upon instilling a volume of
peritoneal dialysate into the peritoneal cavity, osmotic pressure
and a diffusion gradient cause excess fluid and waste products to
leave the blood by crossing the peritoneal membrane and accumulate
in the peritoneal cavity containing the dialysis fluid. After a
sufficient dwell time, the spent peritoneal dialysate together with
the accumulated excess fluid and waste products are drained from
the peritoneal cavity.
[0008] Today, virtually all dialysate for hemodialysis is made at
the site of treatment (in a hemodialysis machine) by mixing (1)
treated water, (2) an acid concentrate, and (3) a base concentrate.
Because the base concentrate typically contains sodium bicarbonate
as the primary basic material, dialysate made by mixing these
ingredients is commonly known as bicarbonate dialysate. Bicarbonate
dialysate is almost universally made in the hemodialysis machine,
through the use of a "three-stream" proportionate pumping mechanism
wherein the treated water, liquid `acid concentrate` and liquid
bicarbonate (base) concentrate are combined. One patient typically
requires 120 liters or more of dialysate for a single hemodialysis
treatment. Chronic kidney failure patients are treated 3 times per
week, 52 weeks per year.
[0009] The concentrates are supplied to the dialysis clinic in two
forms; the `acid concentrate` is generally supplied as a liquid and
the bicarbonate is shipped as a dry powder. The acid concentrate
typically contains sodium chloride, calcium chloride, potassium
chloride, magnesium chloride, dextrose and sufficient acid (acetic
acid) for pH balance. The precise composition of the acid
concentrate to be used in a specific dialysis session is determined
by a doctor's prescription.
[0010] Prior to a patient's treatment session, a jug of liquid acid
concentrate is obtained. Generally, this jug of concentrate is
drawn from a larger tank or drum of the acid concentrate. A staff
member of the dialysis clinic also prepares a jug of sodium
bicarbonate concentrate by mixing a quantity of powdered sodium
bicarbonate with a specific quantity of treated water. Separate
concentrated solutions of `acid` and bicarbonate are necessary
because combining concentrated acid and base solutions would cause
the precipitation of calcium and magnesium carbonates. After proper
mixing, the final dialysate has the concentrations prescribed by
the physician.
[0011] As noted, kidney failure patients accumulate excess fluids
and normally excreted substances in their blood, most notably,
blood urea nitrogen (BUN) and creatinine. In fact, the reduction in
the blood levels of these two substances is generally used to gauge
the efficiency and overall effectiveness of dialysis. Often the
efficiency of dialysis can be compromised by a number of factors,
one of which could be the blockage of dialyzer membrane pores by
clotted blood.
[0012] Additionally, many kidney failure patients suffer from
chronic acidosis because their kidneys are not able to remove acid.
Traditionally, one of the several goals of hemodialysis treatment
is the correction of acidosis by providing higher than normal
amounts of bicarbonate in the dialysate to buffer the excess acid
in the blood. However, despite infusing "extra" bicarbonate during
hemodialysis, normal blood bicarbonate levels are not sustained in
many patients between hemodialysis treatments.
[0013] Accordingly, there is a need in the art for improved
dialysate formulations that increase the efficiency of the
hemodialysis treatment. The present invention is directed to
meeting this need and provides additional related advantages as
disclosed herein.
BRIEF SUMMARY OF THE INVENTION
[0014] The present invention provides compositions, termed
dialysate precursor compositions, which may be diluted with water
and mixed with a base to thereby form a dialysate composition. The
dialysate precursor composition, as well as the dialysate
compositions prepared therefrom, contain citric acid and an
effective amount of a buffering agent selected from acetate and/or
lactate. The buffering agent requires a physiologically acceptable
amount of citrate to maintain the desired pH of the dialysate.
[0015] In one embodiment, the invention provides a dialysate
precursor composition. This composition contains, at a minimum,
water; chloride at a concentration ranging from about 1,000 to
about 7,000 mEq/L; citrate at a concentration ranging from about 20
to about 900 mEq/L; at least one buffering anion selected from
acetate and/or lactate at a concentration ranging from about 0.01
to about 150 mEq/L; and at least one physiologically-acceptable
cation. In a related embodiment, the invention provides a dry
dialysate precursor composition which, upon mixing with water,
provides an aqueous composition having the above-recited components
in the above-recited concentrations. In one embodiment the dry
dialysate precursor composition is a pellet or tablet, while in
another embodiment the dry dialysate precursor composition is a
powder.
[0016] In another embodiment, the invention provides a dialysate
composition. This dialysate composition contains, at a minimum,
treated water; chloride at a concentration ranging from about 20 to
about 200 mEq/L; citrate at a concentration ranging from about 0.5
to about 30 mEq/L; at least one buffering anion selected from
acetate and/or lactate at a concentration ranging from about 0.01
to about 4.5 mEq/L; base including bicarbonate; and at least one
physiologically-acceptable cation. In a related embodiment, the
invention provides a dry dialysate composition which, upon mixing
with water, provides an aqueous composition having the
above-recited components in the above-recited concentrations. In
one embodiment the dry dialysate composition is a pellet or tablet,
while in another embodiment the dry dialysate composition is a
powder.
[0017] In another embodiment, the present invention provides a
method of forming a dialysate precursor composition. The method
includes the step of mixing together treated water, chloride,
citrate, at least one buffering anion selected from acetate and/or
lactate, and at least one physiologically-acceptable cation to
provide a composition having chloride at a concentration ranging
from about 1,000 to about 7,000 mEq/L, citrate at a concentration
ranging from about 20 to about 900 mEq/L, and at least one
buffering anion selected from acetate and lactate at a
concentration ranging from about 0.01 to about 150 mEq/L. In a
related embodiment, the invention provides a method of forming a
dialysate precursor composition which includes the step of mixing
water with a dry dialysate precursor composition comprising the
above-recited components, so as to provide an aqueous composition
having the above-recited component concentrations. In one
embodiment, the dry dialysate precursor composition is a pellet or
tablet, while in another embodiment the dry dialysate precursor
composition is a powder.
[0018] In another embodiment, the present invention provides a
method of forming a dialysate composition. The method includes the
step of mixing the dialysate precursor composition with an aqueous
bicarbonate-containing solution. The dialysate precursor
composition contains, at a minimum, treated water, chloride,
citrate, at least one buffering anion selected from acetate and
lactate, and at least one physiologically-acceptable cation to
provide a concentrate having chloride at a concentration ranging
from about 44 to about 143 mEq/L, citrate at a concentration
ranging from about 1.5 to about 30 mEq/L, and at least one
buffering anion selected from acetate and lactate at a
concentration ranging from about 0.01 to about 3.6 mEq/L.
[0019] In other embodiments, the present invention provides
compositions prepared according to the afore-described methods.
[0020] In another embodiment, the present invention provides an
aqueous acid-concentrate composition which contains water, chloride
at a concentration of about 1,000 to about 7,000 mEq/L; citrate at
a concentration ranging from about 20 to about 900 mEq/L; and
sufficient physiologically-acceptable cations to provide for a
neutral composition. This acid-concentrate composition has a pH of
less than 4, and does not contain any of acetate, bicarbonate or
lactate.
[0021] In a related embodiment, the invention provides a dry
acid-concentrate precursor composition comprising the above-recited
components (absent the water) which, upon mixing with water,
provides the aqueous acid-concentrate composition having the
indicated components in the indicated concentrations. In one
embodiment, the dry acid-concentrate precursor composition is a
pellet or tablet, while in another embodiment the dry
acid-concentrate precursor composition is a powder.
[0022] The magnesium concentration is preferably less than or equal
to 2 mEq/L, and the calcium concentration is preferably less than
or equal to 4.5 mEq/L, and the bicarbonate concentration is
preferably within the range of 25-40 mEq/L. The calcium and
magnesium concentrations should be adjusted to higher values as the
amount of citrate in the composition increases, in order to
compensate for citrate's binding to serum calcium and/or
magnesium.
[0023] In another embodiment, the present invention provides
sterile compositions specifically suited for peritoneal dialysis.
According to one embodiment, the invention provides a peritoneal
dialysate composition comprising treated water, citrate at a
concentration of about 0.5-30 mEq/L; chloride at a concentration of
about 20-200 mEq/L; bicarbonate at a concentration of about 5-100
mEq/L assuming all carbonate-containing species are in the
bicarbonate form, glucose at a concentration of about 10-100 g/L;
and a sufficient number of physiologically-acceptable cations to
neutralize all of the citrate, chloride, bicarbonate, and any other
anionic species that may be present in the composition. In another
embodiment, the invention provides a composition for peritoneal
dialysis as described above, but without any water. This embodiment
thus provides a dry composition, to which sterile water may be
added in order to form a peritoneal dialysate.
BRIEF DESCRIPTION OF THE DRAWING
[0024] The FIGURE is a plot of Dialysate pH (y-axis) vs. Sodium
Acetate Concentration (x-axis), and shows the effect on pH of
adding sodium acetate to dialysate when the bicarbonate concentrate
solution had an initial pH of 8.14.
DETAILED DESCRIPTION OF THE INVENTION
[0025] In one aspect, the present invention provides compositions,
termed dialysate precursor compositions, which contain, or are
prepared from, components including water, chloride, citrate, at
least one buffering anion preferably selected from acetate and/or
lactate, and at least one physiologically-acceptable cation. The
dialysate precursor composition, upon mixing with a base and with
dilution, forms a biocompatible composition that can be used for
either hemodialysis or peritoneal dialysis. In a related aspect,
the invention provides a dry dialysate precursor composition which,
upon mixing with water, provides an aqueous composition having the
above-recited components. In one embodiment the dry dialysate
precursor composition is a pellet or tablet, while in another
embodiment the dry dialysate precursor composition is a powder.
[0026] As discussed in more detail below, the presence of some
buffering anion, e.g., an anion selected from acetate and/or
lactate, in the dialysate precursor composition allows the
dialysate precursor composition to be used as the acid concentrate
in a standard three-stream dialysis machine, along with standard
base (i.e., bicarbonate) concentrate, thereby mitigating problems
associated with fluctuations in the pH of the dialysate during a
dialysis treatment. Absent the buffering anion, the dialysate can
have pH and/or conductivity properties which are outside the ranges
considered acceptable by health care professionals. Prior to a more
extended discussion of the compositions of the invention, and the
properties thereof, the primary ingredients of the compositions
will be described.
[0027] As used herein, "chloride" refers to anionic chloride. Thus,
the term "chloride" includes anionic chloride and the salt forms
thereof, such as may be formed from chloride anion(s) and
physiologically-acceptable cation(s). The term "chloride" is not
intended to include compounds wherein the chloride atom is
covalently bonded to, for example, a carbon atom in an organic
molecule. Exemplary physiologically-acceptable cations include,
without limitation, hydrogen ions (i.e., protons), metal cations,
and ammonium cations. Metal cations are generally preferred, where
suitable metal cations include, but are not limited to, the
cationic forms of sodium, potassium, magnesium and calcium. Of
these, sodium and potassium are preferred, and sodium is more
preferred. When iron or trace element is desirably included in the
composition, the metal cation may be iron cation (i.e., ferric or
ferrous cation) or may be a cation of a trace element, e.g.,
selenium or zinc cation. A composition containing chloride salts
may contain a mixture of physiologically-acceptable cations.
[0028] In one embodiment, the chloride in the precursor dialysate
composition is present at a concentration ranging from about 1,000
to about 7,000 mEq/L, preferably from about 2,000 to about 5,000
mEq/L. In general, the concentrations of the components of present
precursor dialysate composition are individually prescribed by a
physician to reduce, increase, or normalize the concentrations of
various components of the patient's blood, plasma, or serum.
Accordingly, the precise concentration of chloride in the precursor
dialysate composition, and the dialysate composition prepared
therefrom, will be determined by a physician according to
principles known in the art.
[0029] As used herein, "citrate" refers to a citrate anion, in any
form, including citric acid (citrate anion complexed with three
protons), salts containing citrate anion, and partial esters of
citrate anion. Citrate anion is an organic, tricarboxylate with the
following chemical formula:
##STR00001##
Citric acid, which has been assigned Chemical Abstracts Registry
No. 77-92-2, has the molecular formula
HOC(CO.sub.2H)(CH.sub.2CO.sub.2H).sub.2 and a formula weight of
192.12 g/mol. A citrate salt (i.e., a salt containing citrate
anion) is composed of one or more citrate anions in association
with one or more physiologically-acceptable cations. Exemplary
physiologically-acceptable cations include, but are not limited to,
protons, ammonium cations and metal cations. Suitable metal cations
include, but are not limited to, sodium, potassium, calcium, and
magnesium, where sodium and potassium are preferred, and sodium is
more preferred. A composition containing citrate anion may contain
a mixture of physiologically-acceptable cations.
[0030] A partial ester of a citrate anion will have one or two, but
not all three, of the carboxylate (i.e., --COO.sup.-) groups of
citrate anion in an ester form (i.e., --COO--R, where R is an
organic group). In addition to one or two R groups, the partial
ester of a citrate anion will include one or two
physiologically-acceptable cations (so that the total of the R
group(s) and cation(s) equals three). The R group is an organic
group, preferably a lower alkyl.
[0031] The citrate is preferably in association with protons and/or
metal cations. Exemplary of such citrate compounds are, without
limitation, citric acid, sodium dihydrogen citrate, disodium
hydrogen citrate, trisodium citrate, trisodium citrate dihydrate,
potassium dihydrogen citrate, dipotassium hydrogen citrate, calcium
citrate, and magnesium citrate. In one embodiment, the citrate is
present in the dialysate precursor composition in the form of one
or more of citric acid, sodium dihydrogen citrate, disodium
hydrogen citrate, potassium dihydrogen citrate, or dipotassium
hydrogen citrate.
[0032] In a preferred embodiment, citric acid provides the source
for the citrate anions. In this embodiment, the citric acid
functions as the main acidifying agent of the precursor
composition. Citric acid is a relatively inexpensive physiological
acid that, under ambient conditions, is in the form of a dry
chemical powder, crystal, pellet or tablet. Any physiologically
tolerable form of citric acid may be used to introduce citrate
anions to the composition. For instance, the citric acid may be in
the form of a hydrate, including a monohydrate.
[0033] Citrate has been previously recognized to be able to
function as an anti-coagulant in the bloodstream by binding
calcium. Accordingly, the citrate concentration of the dialysate
precursor composition should be selected in view of its
anti-coagulation properties. Unless other measures are taken, the
citrate concentration should not exceed about 900 mEq/L, and is
preferably not more than about 200 mEq/L. When citrate
concentrations of 200-900 mEq/L are employed, the magnesium and/or
calcium concentration of the dialysate precursor composition must
be increased.
[0034] Although the citrate concentration should not be so great
that it detrimentally affects the coagulation properties of blood,
the concentration of citrate should be sufficiently high that it
will be effective to achieve and maintain the pH of the final
dialysate composition at a physiologically-acceptable pH.
Typically, a citrate concentration that is one-quarter or less of
the amount needed to achieve anti-coagulation can provide a
dialysate composition with a physiologically-acceptable pH. Thus,
the present dialysate precursor composition should have a minimum
citrate concentration of about 20 mEq/L in order to provide the
desired dialysate pH. In one embodiment, the dialysate precursor
composition contains citrate at a concentration ranging from about
20 to about 900 mEq/L and in a preferred embodiment the composition
contains citrate at a concentration ranging from about 70 to about
150 mEq/L. In a related embodiment, the invention provides a dry
dialysate precursor composition which, upon mixing with water,
produced a dialysate precursor composition that contains citrate at
a concentration ranging from about 20 to about 900 mEq/L and in a
preferred embodiment the composition contains citrate at a
concentration ranging from about 70 to about 150 mEq/L.
[0035] Although citrate functions as an acidifying agent to lower
the pH of a dialysate composition, in one aspect the present
invention introduces a buffering anion to the dialysate precursor
composition in order to maintain the pH of the final dialysate
composition within a physiologically-acceptable range. As used
herein, "buffering anion" refers to a physiologically acceptable
anion that adjusts and regulates the pH of a composition. Suitable
buffering anions include, for example, acetate, lactate, and
mixtures thereof (i.e., acetate and/or lactate), which are
compounds that will minimize changes in hydrogen ion concentration
of a dialysate composition. As used herein, the phrase "lactate
and/or acetate" means that either lactate alone, acetate alone, or
a mixture of lactate and acetate may be used, or present, in the
composition.
[0036] As used herein, "acetate" refers to an acetate anion, in any
form, including acetic acid and salts of acetic acid. Acetate is an
organic, monocarboxylate with the formula H.sub.3C--COO.sup.-. The
acetate salt is composed of one or more acetate anions in
association with one or more physiologically-acceptable cations.
Exemplary physiologically-acceptable cations include, but are not
limited to, protons, ammonium cations and metal cations, where
metal cations are preferred. Suitable metal cations include, but
are not limited to, sodium, potassium, magnesium and calcium, where
sodium and potassium are preferred, and sodium is more
preferred.
[0037] Exemplary acetate compounds of the present invention
include, but are not limited to, acetic acid, sodium acetate,
sodium acetate trihydrate, potassium acetate, calcium acetate,
calcium acetate monohydrate, magnesium acetate, and magnesium
acetate tetrahydrate. In one embodiment, the acetate of the
dialysate precursor composition is present in the form of sodium
acetate or potassium acetate, and in a preferred embodiment,
acetate is in the form of sodium acetate.
[0038] As used herein, "lactate" refers to a lactate anion, in any
form, including lactic acid and salts of lactic acid. Lactate is an
organic, monocarboxylate with the formula
H.sub.3C--CH(OH)--COO.sup.-. A lactate salt is composed of one or
more lactate anions in association with one or more
physiologically-acceptable cations. Exemplary
physiologically-acceptable cations include, but are not limited to,
protons, ammonium cations and metal cations, where metal cations
are preferred. Suitable metal cations include, but are not limited
to, sodium, potassium, magnesium and calcium, where sodium and
potassium are preferred, and sodium is more preferred. When iron or
trace element is desirably included in the composition, the metal
cation may be iron cation (i.e., ferric or ferrous cation) or may
be a cation of a trace element, e.g., selenium or zinc cation.
[0039] Exemplary lactate compounds of the present invention
include, but are not limited to, lactic acid, sodium lactate,
potassium lactate, calcium lactate and magnesium lactate
trihydrate. In one embodiment, the lactate of the dialysate
precursor composition is present in the form of sodium lactate or
potassium lactate, and most preferably lactate is in the form of
sodium lactate. When iron or trace element is desirably included in
the composition, the lactate may be complexed with iron (i.e.,
ferric or ferrous lactate) or may be complexed with a trace
element, e.g., selenium or zinc cation.
[0040] In general, the dialysate precursor composition will
typically contain more equivalents of citrate than equivalents of
buffering anion. The precursor composition preferably contains more
equivalents of citrate than equivalents of acetate, lactate, or
lactate+acetate. In one embodiment, the dialysate precursor
composition contains citrate at a concentration ranging from about
20 to about 900 mEq/L together with a buffering anion selected from
acetate and/or lactate at a concentration ranging from about 0.01
to about 150 mEq/L. In a preferred embodiment the composition
contains citrate from about 70 to about 150 mEq/L and a buffering
anion selected from acetate and/or lactate at a concentration
ranging from about 0.3 to about 125 mEq/L. In a related embodiment,
the present invention provides dry compositions (e.g., pellets,
tablets, powder) which upon mixing with water provide the dialysate
precursor compositions described above.
[0041] As the amount of citrate in the dialysate precursor
composition is increased, it tends to lower the pH of the dialysate
made with the precursor. With a lower dialysate pH, there is not as
much need to buffer the precursor to ensure that the dialysate pH
does not rise to a physiologically unacceptable level. Therefore,
as a general rule, as higher equivalents of citrate are used in the
dialysate precursor composition, less equivalents of buffering
anion are required. Conversely, as less equivalents of citrate are
used in the dialysate precursor composition, more equivalents of a
buffering anion are required.
[0042] As used herein, the phrase "physiologically-acceptable
cations" refers to cations normally found in the blood, plasma, or
serum of a mammal, or cations that may be tolerated when introduced
into a mammal. Suitable cations include protons, ammonium cations
and metal cations. Suitable metal cations include, but are not
limited to, the cationic forms of sodium, potassium, calcium, and
magnesium, where sodium and potassium are preferred, and sodium is
more preferred. An ammonium cation, i.e., a compound of the formula
R.sub.4N.sup.+ where R is hydrogen or an organic group, may be used
so long as it is physiologically acceptable. In a preferred
embodiment, the cation is selected from hydrogen (i.e., proton),
sodium, potassium, calcium, magnesium, and combinations
thereof.
[0043] When the pH of a dialysate composition begins to increase
(i.e., the dialysate becomes more basic) during the course of a
dialysis treatment, the buffering anion, when present in an
effective amount, prevents the pH of the dialysate composition from
rising beyond a physiologically-acceptable range. For compositions
having the citrate concentrations described above, and to provide
the desired buffering effect, the precursor composition should
contain from about 0.01 to about 150 mEq/L of buffering anion,
preferably selected from acetate, lactate and mixtures thereof. In
a preferred embodiment, the precursor composition contains from
about 0.3 to about 125 mEq/L of acetate and/or lactate. In one
embodiment, the buffering anion is a mixture of acetate and
lactate. In another embodiment, the buffering anion is acetate, and
lactate is not present in the composition. In another embodiment,
the buffering anion is lactate, and acetate is not present in the
composition.
[0044] With peritoneal dialysate, in order to facilitate the
diffusion between blood and dialysate, it is desirable to maintain
an osmotic gradient between the fluids by adding an osmotic agent
to the dialysate. The presence of an osmotic agent in the
peritoneal dialysate will encourage excess fluid and metabolic
waste byproducts to flow from the blood and into the dialysate. A
suitable osmotic agent for the precursor dialysate composition is
sugar. The sugar is preferably selected from glucose (e.g.,
dextrose), poly(glucose) (i.e., a polymer made from repeating
glucose residues, e.g., icodextrin, made from repeating dextrose
units), or fructose. While it is possible to make a dialysate
precursor with no sugar, if sugar is to be added to the dialysate
composition, it is generally dextrose. It is further appreciated
that any biocompatible, non-sugar osmotic agent that functions as
an equivalent could be a viable substitute. The sugar is typically
present in the dialysate precursor composition at a concentration
of less than about 2,700 g/L.
[0045] A patient's blood serum contains several components
including, for example, proteins, carbohydrates, nucleic acids, and
various ions. Typically, a dialysate composition prescribed by a
physician is chosen to reduce, increase, or normalize the
concentration of a particular component in the serum. Several
cations may be prescriptively included as part of the precursor
dialysate composition. Suitable cations may include, for example,
sodium, potassium, calcium and magnesium. In the dialysate
precursor composition, the preferred concentration range for sodium
is from about 2,000 to about 5,000 mEq/L. The preferred
concentration range for potassium is less than about 250 mEq/L. The
preferred concentration range for calcium is less than about 250
mEq/L. The preferred concentration range for magnesium is less than
about 100 mEq/L. As used herein, a concentration of less that about
a recited value includes zero. In a related embodiment, the present
invention provides dry compositions (e.g., tablets, pellets,
powder, etc.) which upon mixing with water provide a dialysate
precursor composition having the sodium, potassium, calcium, and
magnesium concentrations recited above.
[0046] As used herein, "mEq/L" refers to the concentration of a
particular dialysate component (solute) present in proportion to
the amount of water present. More specifically, mEq/L refers to the
number of milli-equivalents of solute per liter of water.
Milli-equivalents per liter are calculated by multiplying the moles
per liter of solute by the number of charged species (groups) per
molecule of solute, which is then multiplied by a factor of 1,000.
As an example, when 10 grams of citric acid are added to a liter of
water, the citric acid is present at a concentration of 10 g/L.
Anhydrous citric acid has a molecular weight of 192.12 g/mol;
therefore, the number of moles per liter of citric acid, and
consequently citrate anion (since there is one mole of citrate
anion per mole of citric acid), is 10 g/L divided by 192.12 g/mol,
which is 0.05 mol/L. Citrate anion has three negatively charged
species in the form of carboxylate groups. Accordingly, the citrate
concentration of 0.05 mol/L is multiplied by three and then by
1,000, in order to provide a concentration of citrate in terms of
mEq/L, which in the present example is 156 mEq/L of citrate
anion.
[0047] A preferred water of the invention is treated in order that
it is essentially pyrogen-free and sterile, and at least meets the
purity requirements established by the Association for the
Advancement of Medical Instrumentation (AAMI) for dialysate
compositions. The water may also be referred to as treated water or
AAMI-quality water. A monograph describing water treatment for
dialysate, monitoring of water treatment systems, and regulation of
water treatment systems is available from AAMI (Standards
Collection, Volume 3, Dialysis, Section 3.2 Water Quality for
Dialysis, 3 ed., 1998, AAMI, 3330 Washington Boulevard, Arlington,
Va. 22201) or through the Internet at http://www.aami.com. In
addition, all of the other components of the precursor dialysate
composition of the present invention are preferably at least United
States Pharmacopeia (USP)-grade purity, which is generally a purity
of about 95%. The purity of the components is preferably at least
about 95%, more preferably at least about 98%, and more preferably
at least about 99%.
[0048] The dialysate precursor composition of the present invention
will typically have a pH ranging from about 1 to about 6.5, more
typically from about 1 to about 4, more typically from about 2 to
about 4, at a temperature of about 15.degree. C. to about
40.degree. C., before dilution with treated water and base to
afford the dialysate composition.
[0049] In a preferred embodiment, the dialysate precursor
composition contains components including chloride at a
concentration ranging from about 2,000 to about 5,000 mEq/L;
citrate at a concentration ranging from about 70 to about 150
mEq/L; acetate and/or lactate at a total concentration ranging from
about 0.3 to about 125 mEq/L; at least one
physiologically-acceptable cation selected from hydrogen, sodium at
a concentration ranging from about 2,000 to about 5,000 mEq/L,
potassium at a concentration of less than about 250 mEq/L, calcium
at a concentration of less than about 250 mEq/L, and magnesium at a
concentration of less than about 100 mEq/L; and glucose (preferably
dextrose) at a concentration of less than about 2,700 g/L, where
the composition meets or exceeds the AAMI standard set for
dialysate. In one embodiment, the above-listed ingredients are the
only active ingredients in the composition. In a related
embodiment, the present invention provides a dry composition which,
upon mixing with water, provides the dialysate precursor
composition having the components and component concentrations
indicated above.
[0050] The present invention provides a method of forming the
precursor dialysate composition as described above. In this method,
ingredients are mixed together so as to provide the dialysate
precursor composition. Thus, a source of chloride, a source of
citrate, and a source(s) of buffering anion (e.g., acetate and/or
lactate) are mixed together with treated water, in amounts which
ultimately provide the desired concentration of each, as set forth
above. The non-aqueous components of the precursor dialysate
composition may be pre-mixed and in the form of a powder, pellet,
tablet or other dry form, which is then readily mixed with water so
as to form the precursor dialysate composition. Suitable sources
for these ingredients are well known in the art. Indeed, the
chemical characteristics for the compounds used in the present
invention, such as molecular weight and solubility, are available
in the art such that one of ordinary skill in the art will know how
to prepare the composition of the present invention. See, e.g., the
Sigma and Aldrich catalogs from Sigma-Aldrich (Milwaukee, Wis.;
http://www.sial.com).
[0051] For example, the chloride source may be any of hydrochloric
acid, sodium chloride, potassium chloride, magnesium chloride,
ammonium chloride, or the like. The citrate source may be any of
citric acid, sodium dihydrogen citrate, disodium hydrogen citrate,
trisodium citrate, trisodium citrate dihydrate, potassium
dihydrogen citrate, dipotassium hydrogen citrate, calcium citrate,
magnesium citrate, or the like. The acetate source may be any of
acetic acid, sodium acetate, sodium acetate trihydrate, potassium
acetate, calcium acetate, calcium acetate monohydrate, magnesium
acetate, magnesium acetate tetrahydrate, and the like. The lactate
source may be any of lactic acid, sodium lactate, potassium
lactate, calcium lactate, magnesium lactate trihydrate, and the
like. Any or all of these chemicals are commercially available, in
USP-grade if desired, from many chemical supply houses including,
for example, Aldrich Chemical Co., Milwaukee Wis. The treated water
may be obtained by following standard purification techniques,
including, for example, distillation and reverse osmosis.
Alternatively, the treated water may be purchased commercially.
Such treated water is used in all, or nearly all, dialysis clinics
and accordingly is well known to one of ordinary skill in the
art.
[0052] In one embodiment, the invention provides a method of
forming a dialysate precursor composition which includes the step
of mixing water, chloride, citrate, at least one buffering anion
selected from acetate and/or lactate, and at least one
physiologically-acceptable cation, to provide a composition having
chloride at a concentration ranging from about 1,000 to 7,000
mEq/L, citrate at a concentration ranging from about 20 to 900
mEq/L, and at least one buffering anion selected from acetate
and/or lactate at a total concentration ranging from about 0.01 to
150 mEq/L. The non-aqueous components of the dialysate precursor
composition may be pre-mixed and in the form of a dry powder,
pellet, tablet, etc., so that the method entails mixing water with
this dry pre-mixed composition.
[0053] In a preferred embodiment, sources of water, chloride,
citrate, acetate and physiologically-acceptable cations are mixed
so as to provide a composition having water, chloride at a
concentration ranging from about 2,000 to about 5,000 mEq/L;
citrate at a concentration ranging from about 70 to about 150
mEq/L; acetate at a concentration ranging from about 0.3 to about
125 mEq/L; at least one physiologically-acceptable cation selected
from hydrogen, sodium at a concentration ranging from about 2,000
to about 5,000 mEq/L, potassium at a concentration of less than
about 250 mEq/L, calcium at a concentration of less than about 250
mEq/L, magnesium at a concentration of less than about 100 mEq/L;
and glucose at a concentration of less than about 2,700 g/L, where
the composition meets or exceeds the AAMI-quality standard set for
dialysate.
[0054] In another aspect, the present invention provides a
dialysate composition. The dialysate composition may, for example,
be prepared from the dialysate precursor composition described
above by adding treated water and a base, preferably bicarbonate,
to the precursor composition. Upon the addition of base and water,
the dialysate precursor composition provides a composition suitable
for performing dialysis. As an alternative, a dry composition as
also described previously may be combined with water and base in
order to prepare the dialysate composition.
[0055] For example, bicarbonate concentrate, or diluted bicarbonate
concentrate, may be added to the dialysate precursor composition,
or diluted dialysate precursor composition, to provide a dialysate
composition according to the present invention. Typically, one
volume part of dialysate precursor composition is diluted with
between 33 and 45 parts of diluted base concentrate, to provide the
dialysate composition. The dialysate precursor will contain citrate
(as the primary acidic ingredient of the acid concentrate),
bicarbonate (as the primary basic ingredient of the base
concentrate) and buffering anion preferably selected from acetate
and/or lactate.
[0056] In one embodiment, the dialysate composition contains
ingredients including treated water; chloride at a concentration
ranging from about 20 to about 200 mEq/L; citrate at a
concentration ranging from about 0.5 to about 30 mEq/L; at least
one buffering anion selected from acetate and/or lactate at a
concentration ranging from about 0.01 to about 4.5 mEq/L;
bicarbonate; and at least one physiologically-acceptable
cation.
[0057] In one embodiment, the dialysate composition includes one or
more sugars selected from glucose (preferably dextrose),
poly(glucose) (preferably, poly(dextrose), e.g., icodextrin), and
fructose at a concentration of less than about 45 g/L. Instead, or
in addition to sugar, the dialysate composition may contain one or
more amino acids. Preferably, the dialysate composition contains
water that meets or exceeds the purity requirements established by
AAMI for dialysate and all other components have at least USP-grade
purity. In another preferred embodiment, the dialysate composition
has a pH of about 5 to about 8.5 at a temperature of about
25.degree. C. to about 40.degree. C., and more typically has a pH
of about 6.4 and 7.6 at this temperature range, and preferably has
a pH of about 7.2 to about 7.4.
[0058] In other embodiments, the dialysate composition contains
ingredients including water, chloride at a concentration ranging
from about 40 to about 150 (more preferably, from about 60 to about
120) mEq/L; citrate at a concentration ranging from about 1.5 to
about 4.5 (more preferably, from about 2 to about 3) mEq/L; acetate
and/or lactate at a total concentration ranging from about 0.01 to
about 4.0 (more preferably, from about 0.2 to 0.5) mEq/L;
bicarbonate at a concentration ranging from about 25 to about 45
mEq/L; at least one physiologically-acceptable cation selected from
hydrogen, sodium at a concentration ranging from about 60 to about
190 (more preferably, from about 70 to about 150) mEq/L, potassium
at a concentration of less than about 5 mEq/L, calcium at a
concentration of less than about 5 mEq/L, and magnesium at a
concentration of less than about 2 mEq/L; and glucose (preferably,
dextrose) at a concentration of less than about 45 (preferably,
less than about 8) g/L, where the combined composition meets or
exceeds the AAMI-quality standard set for dialysate.
[0059] In the dialysate compositions of the present invention,
including the precursors thereto, for either hemodialysis or
peritoneal dialysis, in one embodiment of the invention the
composition includes iron. Patients undergoing dialysis are
oftentimes iron deficient, where iron deficiency is associated with
anemia and other undesirable medical conditions. Currently, iron
deficiency is most commonly addressed by either oral iron
supplementation programs or by parenteral administration of iron.
However, oral iron supplementation programs sometimes cause adverse
gastrointestinal effects, and there is also the difficulty that
patients do not rigorously follow the program. Parenteral
administration of iron overcomes certain difficulties associated
with oral iron administration and is the standard method if the
patient is on peritoneal dialysis. For hemodialysis patients it is
injected into the venous blood line of the dialysis apparatus
during treatment, which adds inconvenience and cost. One aspect of
the present invention addresses these problems by providing
iron-containing dialysis compositions. As used in this context, the
term "iron" refers to both the ferric and ferrous forms of iron, as
well as complexes of iron.
[0060] The iron may be introduced into the composition in any
convenient form that is also compatible with the well-being of the
patient (see, e.g., "NKF-DOQI clinical practice guidelines for the
treatment of anemia of chronic renal failure" Am J. Kidney Dis.
30:S192-S237, 1997). For example, iron dextran (ferric hydroxide
dextran complex, CAS Registry No. 9004-66-4) is currently
administered to hemodialysis patients via parenteral
administration. (see, e.g., "Iron dextran treatment in peritoneal
dialysis patients on erythropoietin" Perit. Dial. Bull. 8:464-466,
1992; and Goldberg, L., "Pharmacology of parenteral iron
preparations" Iron in Clinical Medicine 78:74-92, 1958). In lieu
of, or in addition to, dextran, the iron may be complexed with
other saccharrides or polysaccharides, e.g., iron saccharate or
gluconate complex. Any of these iron saccharide complexes may be
included in a dialysate composition of the present invention. As
another example, the iron may be introduced via ferric
pyrophosphate (see, e.g., Gupta, A., et al. "Dialysate iron
therapy: Infusion of soluble ferric pyrophosphate via the dialysate
during hemodialysis" Kidney International 55:1891-1898, 1999). In
order to create a water-soluble form of ferric pyrophosphate, the
ferric pyrophosphate may be prepared by chemical reaction with
citric acid and sodium hydroxide. As a final example, the iron may
be introduced to the dialysate composition via either or both of
ferric citrate (CAS Registry No. 3522-50-7) or ferrous citrate. In
one aspect of the invention, the iron is introduced to the
dialysate via an iron salt of citrate.
[0061] Regardless of the form in which the iron is added to the
dialysate, the amount of iron being added should be a
therapeutically effective amount. This amount will vary somewhat
depending on the specific condition of the patient and the goals of
the attending physician. However, generally, an iron concentration
in dialysate ranging from 0.1 to 300 micrograms/deciliter will be a
suitable concentration. Because this amount will typically vary
from patient to patient, a commercial citrate-containing product
may be prepared that does not contain any iron, and the product may
be "spiked" with the desired amount of iron in the hospital or
other site where the patient is undergoing the dialysis
treatment.
[0062] In the dialysate compositions of the present invention,
including the precursors thereto, for either hemodialysis or
peritoneal dialysis, in one embodiment of the invention the
composition includes one or more trace elements. Studies have shown
that dialysis, and particularly maintenance dialysis, causes loss
of trace elements from the patient undergoing the dialysis. The
present invention provides compositions and methods to offset that
loss of trace elements by incorporating trace elements into a
composition of the present invention.
[0063] Any one or more trace elements may be included in a
composition of the present invention (see, e.g., Zima, T., et al.,
Blood Purif. 17(4):187-198, 1999 and Zima, T. et al. "Trace Blood
Purif. 16(5):253-260, 1998). For example, selenium may be included
in a composition of the present invention (see, e.g., Krizek, M. et
al. "Influence of hemodialysis on selenium blood levels" Sb Lek
101(3):241-248, 2000; and Napolitano G., "Thyroid function and
plasma selenium in chronic uremic patients on hemodialysis
treatment" Biol. Trace Elem. Res. 55(3):221-30, Dec. 1996). Another
trace element that may be included in a composition of the present
invention is zinc. Chromium, manganese and molybdenum are yet three
other trace elements that may be included in the dialysate
composition.
[0064] The trace element may be added to the composition via any
salt or complex of the element. For example, regardless of the
identity of the trace element, in one aspect of the invention the
element may be added to a composition of the present invention via
its citrate salt. However, other suitable forms may be used, e.g.,
zinc sulfate for zinc, selenium sulfide for selenium. The amount of
trace metal to be included in a composition of the present
invention should be selected in view of the specific condition of
the patient and the goal of the attending physician. However,
generally, the Recommended Daily (or Dietary) Allowance (RDA) of
trace elements, as set forth by the Food and Nutrition Board of the
National Academy of Sciences/National Research Council, is a good
guideline to follow (see, e.g., Recommended Dietary Allowances:
National Academy of Sciences; 10th ed., 1989; see also Dietary
Reference Intakes (DRIs): National Academy of Sciences, 1997).
Because this amount may vary from patient to patient, a commercial
citrate-containing product may be prepared that does not contain
any trace elements, and the product may be "spiked" with the
desired trace elements, in the desired amounts, in the hospital or
other site where the patient is undergoing the dialysis
treatment.
[0065] In another aspect, the present invention provides a method
of forming a dialysate composition. In a preferred embodiment, the
method includes combining the dialysate precursor composition, as
described above, with a base concentrate, preferably a bicarbonate
base concentrate, and treated water as needed to provide prescribed
concentrations of solutes in the dialysate. The base concentrate
contains water, bicarbonate, and has a pH of greater than 7. The pH
will be greater than 7 because of the presence, in the concentrate,
of one or more "bases." Base concentrate is currently used in most
dialysis clinics. The base in a typical base concentrate is
bicarbonate, also known as hydrogen carbonate, having the chemical
formula HCO.sub.3. Bicarbonate carries a net negative charge, and
accordingly will be associated with a positively charged species.
Suitable positively charged species include
physiologically-acceptable metal cations such as the cationic forms
of sodium, potassium, calcium and magnesium.
[0066] The base from which the base concentrate is almost
universally prepared in dialysis clinics is sodium bicarbonate, and
this is the preferred base in the present compositions and methods.
The bicarbonate concentrate in a dialysate is preferably from about
25 to 40 mEq/L. Acetate base is not a preferred base.
[0067] Optionally, the sodium bicarbonate in a base concentrate may
be replaced, in part, with a different physiologically-acceptable
base. The anionic portion of a suitable replacement for sodium
bicarbonate may be, for example, carbonate, lactate, citrate and
acetate. Accordingly, the base for a base concentrate may be
selected from the salt forms of any of bicarbonate and, optionally,
carbonate, lactate, citrate and acetate. Also present in the salt
forms will be one or more physiologically-acceptable cations
selected from sodium, potassium, calcium and magnesium. These salts
and acids are electronically neutral, i.e., there are an equal
number of negative and positive charges.
[0068] Preferably, the dialysate precursor composition and the base
concentrate are mixed so as to arrive at a dialysate composition
that contains ingredients including water, chloride at a
concentration ranging from about 40 to about 150 (more preferably,
from about 60 to about 120) mEq/L; citrate at a concentration
ranging from about 1.5 to 15.0, preferably from about 1.5 to about
4.5 (more preferably, from about 2 to about 3) mEq/L; acetate
and/or lactate at a total concentration ranging from about 0.01 to
about 4.0 (more preferably, from about 0.2 to 0.5) mEq/L;
bicarbonate at a concentration ranging from about 25 to about 45
mEq/L; at least one physiologically-acceptable cation selected from
hydrogen, sodium at a concentration ranging from about 60 to about
190 (more preferably, from about 70 to about 150) mEq/L, potassium
at a concentration of less than about 5 mEq/L, calcium at a
concentration of less than about 5 mEq/L, and magnesium at a
concentration of less than about 2 mEq/L; and glucose (preferably,
dextrose) at a concentration of less than about 45 (preferably,
less than about 8) g/L, where the combined composition meets or
exceeds the AAMI-quality standard set for dialysate. Higher
concentrations of citrate could typically be used when a patient is
simultaneously infused with excess calcium.
[0069] In dialysate compositions of the invention, the
citrate-containing dialysate precursor composition is combined with
the base concentrate so as to arrive at a final dialysate
composition having a pH in the physiological range of 5 to 8.5, and
preferably from about 7.2 to about 7.4.
[0070] In another aspect, the present invention provides an aqueous
acid-concentrate composition useful in hemodialysis that contains,
at a minimum, water, chloride, citrate, and cations to provide for
a neutral (i.e., no net charge) composition, but does not contain
any of bicarbonate, acetate or lactate. The water is "treated
water" as defined herein, or a water of even greater purity, and
each of the chloride and citrate is USP-grade quality or better
(for example, reagent grade, preferably of at least 99% purity). In
a related aspect, the aqueous acid-concentrate composition is
prepared from water and a solid composition that, upon mixing with
water, affords the aqueous acid-concentrate composition having the
components described above. Thus, the present invention also
provides, in one aspect, this solid composition.
[0071] The aqueous acid-concentrate composition contains chloride
at a concentration of about 1,000 to about 7,000, preferably of
from about 2,000 to about 5,000 mEq/L; citrate at a concentration
ranging from about 20 to about 200, preferably from about 70 to
about 150 mEq/L; and sufficient physiologically-acceptable cations
to provide for a neutral (i.e., no net charge) composition, where
the composition has a pH of less than 4, preferably between about 2
and about 3, and more preferably about 2.2 to 2.8, and does not
contain any of bicarbonate, acetate, or lactate. The present
invention also provides the same composition in a water-free form
which, upon mixing with water, will form the aqueous
acid-concentrate composition described above. The water-free form
may be in the form of, e.g., a pellet, tablet or powder.
[0072] Although this aqueous acid-concentrate composition does not
contain any of bicarbonate, acetate or lactate, it is still
usefully employed in dialysate manufacture. For instance, it
provides a convenient stock solution to which may be added bases
and/or salts. Since it is a liquid, it is conveniently employed as
the acid concentrate in traditional dialyzers that employ the
three-stream proportionate pumping mechanism for making dialysate.
Care should, however, be taken when combining base, such as
bicarbonate, with the aqueous acid-concentrate composition, in
order that the desired pH of the final dialysate is obtained.
[0073] In a related embodiment, the invention provides a method of
preparing dialysate, wherein a basic solution containing water and
at least one of bicarbonate, carbonate, acetate, lactate, and
citrate having a pH of greater than 7 is mixed with the aqueous
acid-concentrate composition described above, i.e., an acidic
solution having a pH of less than 4 containing, at a minimum,
chloride, citrate, and cations, the cations providing for an
electronically neutral composition, where this acidic solution does
not contain any of bicarbonate, acetate or lactate. According to
this method, the relative amounts of basic and acidic solutions
that are combined should be carefully tailored so as to achieve a
desired dialysate pH, at all times throughout a dialysis treatment
session. Typically, that desired dialysate pH is within the range
of 6.8 to 7.8.
[0074] While citric acid-containing hemodialysate compositions are
known in the art, see U.S. Pat. No. 5,252,213 of Ahmad et al., such
compositions are disclosed as dry pellets (or other like solid
form) which are dissolved in water to provide the hemodialysate
composition. Those compositions provide a convenient source of all
of the components of a hemodialysate composition, and are intended
to be combined with water and essentially no other ingredients,
before being used in a hemodialysis treatment. Thus, each pellet
contains both the acidic and basic components of a hemodialysate
composition which ensures the pH of the resulting
hemodialysate.
[0075] The present invention makes an aqueous acid concentrate that
may be used in the preparation of either hemodialysate or
peritoneal dialysate. The citric acid concentrate is intended to be
combined with treated water and base concentrate, as is currently
the practice in dialysis clinics, so as to afford the dialysate
composition. In clinics, the pH of the base concentrate, which
typically contains sodium bicarbonate, can vary widely and affect
the resulting dialysate pH. Therefore, when using a citric
acid-containing acid concentrate in the manner according to the
present invention, the concentrate should contain a buffering agent
in order to maintain the resulting dialysate pH within a
pre-determined, physiologically-acceptable range throughout the
duration of the dialysis treatment. Buffering is required because
increasing the amount of citric acid to lower the dialysate pH may
cause a significant decrease in serum calcium concentration. This
need for a buffer with citric acid concentrate is a departure from
the practice in the art.
[0076] Most dialysates in use today use acetic acid as the
acidifying agent to keep the pH of the final dialysate within an
acceptable physiological range. As noted above, the `acid
concentrate` that is used in most hemodialysis treatments today is
shipped as a liquid. The concentrate is in liquid form because
acetic acid is a liquid acid. Although this solution is far more
concentrated than the final dialysate which is actually used to
purify a patient's blood (it can be as much as 45 times more
concentrated), still three-quarters of its weight and volume is
water. The present invention utilizes citric acid, rather than
acetic acid, as the main acidic material in an acid
concentrate.
[0077] In an acid concentrate that contains citrate, the citrate
will be primarily in the form of citric acid. There are certain
ramifications of using citric acid in an acid concentrate for
dialysate. For example, citric acid forms citrate in the blood
which binds with free magnesium and calcium. In fact, the strong
binding of calcium with citrate is used by blood banks to prevent
clotting in donated blood. While the level of citric acid used in
the dialysate of the present invention is only a fraction (less
than one-quarter) of the amount needed to achieve measurable
anticoagulation, medical prudence dictates using the least amount
of citric acid possible in a dialysate in order to minimize
undesired calcium binding in the blood. When dialysate is prepared
from 45.times. dilution of precursor dialysate, and the precursor
dialysate has citrate concentrations within the range of 200-900
mEq/L, then the precursor preferably has elevated levels of calcium
and/or magnesium to compensate for the extent to which citrate will
bind serum calcium and magnesium.
[0078] The amount of citrate present in the acid concentrate of the
invention should be the least amount necessary to achieve a final
dialysate pH within the range of 7.2 to 7.4. We have found that
using about 7 grams citric acid per liter of water in an acid
concentrate (providing a concentration equal to 2.4 mEq/L) would
minimize the calcium binding and achieve an acceptable dialysate
pH.
[0079] However, the use of citrate in an acid concentrate led to an
intermittent problem when the dialysate was used in a clinical
setting. Generally, late in a dialysis session (usually in the last
hour of treatment) some dialysis machines would sound an alarm due
to high pH. This problem was traced to the base solution.
[0080] Bicarbonate is the basic material present in most base
solutions. In most dialysis clinics, the bicarbonate solution is
made by the clinic staff just before use. The procedure often can
involve pouring a pre-determined amount of sodium bicarbonate
(typically one package) into a jug, adding a measured amount of
water and manually mixing (usually by shaking the container). Any,
some, or all of the following factors may cause variations in the
pH of the bicarbonate from the expected standard: the amount of
water added can be more or less than specified, the mixing can be
insufficient to thoroughly put all the sodium bicarbonate powder
into solution, the container could be left sitting for a period
before use, or the patient has a long dialysis treatment.
[0081] When carefully measuring and adequately mixing the
bicarbonate, the pH of the concentrated solution was 7.85
(.+-.0.05). However, in practice, samples of bicarbonate
concentrate that are prepared by clinic staff had a range of pH
values from 7.78 to 8.13. Furthermore, the pH of the residual
bicarbonate concentrates that had just been used for a hemodialysis
treatment were found to range from 7.9 to 8.24. We speculate that
this variation in pH, most noticeably observed in the `spent`
dialysate, may be from any one of, or a combination of, the
following factors: [0082] Insufficient water was added to the base
concentrate, causing a higher than desired concentration of
bicarbonate. [0083] Inadequate mixing of the powder and water,
allowing some settling of the powder and therefore a more
concentrated bicarbonate solution and rising pH late in the
dialysis treatment (at which time the powder has completely
dissolved). [0084] The bicarbonate concentrate releases carbon
dioxide over time, thereby causing slowly increasing pH.
[0085] One way to ensure against the pH rising to the alarm
threshold during a dialysis treatment is to increase the amount of
acid used, which causes a more acidic dialysate. However,
increasing the amount of citric acid also increases the amount of
calcium binding--accordingly, this approach must be used with
caution. An alternative approach taken according to the present
invention is to mitigate the effects of an increase in dialysate pH
which is caused by a rising pH of the bicarbonate concentrate,
through inclusion of a buffering agent in the acid concentrate.
[0086] Acetate and/or lactate were selected as the preferred
buffering agents in the present invention. Each of these anions is
found naturally in the blood of dialysis patients. Sodium acetate
is a preferred buffer because it contains the same ingredients,
sodium and acetate, that are in virtually all current dialysates
(provided from the sodium chloride and acetic acid).
[0087] Surprisingly, there is not a linear relationship between the
amount of sodium acetate buffer present in the acid concentrate and
the pH of the final dialysate solution. It might be expected that
adding increasing amounts of this acidic buffer to an acid
concentrate would cause a linear decrease in the pH of the final
solution. However, this is not the case. Within a narrow range the
sodium acetate causes a significant decrease in the pH of the
dialysate. However, this buffering action of the sodium acetate is
only observed when the pH of the bicarbonate concentrate exceeds
8.0. At higher pH values of the bicarbonate concentrate, the
buffering action of the acetate is more apparent.
[0088] This effect is shown in the FIGURE. The chart of the FIGURE
illustrates the resulting dialysate pH obtaining using a relatively
high bicarbonate concentration at pH 8.14 combined with treated
water and the present invention's dialysate precursor using 2.4
mEqL of citrate and increasing the sodium acetate concentration
from 0 to 3.5 grams per liter. As shown in the FIGURE, increasing
the concentration of sodium acetate beyond a certain point does not
increase the sodium acetate's buffering action nor does it make the
buffering action apparent at lower values of bicarbonate pH. While
not wishing to be bound by theory, the following is suggested to
explain the surprising effect of using acetate in the acid
concentrates of the invention.
[0089] Citric acid is a multi-protic acid. It contains three labile
hydrogen atoms that can contribute to the acidity of a solution.
There is a separate equilibrium associated with the liberation of
each hydrogen ion:
H.sub.3A H.sup.++H.sub.2A.sup.- K.sub.a1=7.10.times.10.sup.-4 at
20.degree. C. (pKa=3.14)
H.sub.2A.sup.-H.sup.++HA.sup.2- K.sub.a2=1.68.times.10.sup.-6 at
20.degree. C. (pKa=4.77)
HA.sup.2-H.sup.++A.sup.3- K.sub.a3=6.4.times.10.sup.-6 at
20.degree. C. (pKa=6.39)
where A represents the citrate anion. At a pH greater than 7 almost
all of the citric acid is dissociated and the predominant species
are H.sup.+ and A.sup.3-.
[0090] Acetic acid is a monoprotic acid, i.e., it contributes only
one labile hydrogen atom to the solution and there is only one
equilibrium constant for the equilibrium:
HAcH.sup.++Ac.sup.- K.sub.a=1.76.times.10.sup.-6 at 25.degree. C.
(pKa=4.75)
where Ac represents the acetate anion. When sodium acetate (NaAc)
is introduced to aqueous solution it dissolves completely into
sodium ions (Na.sup.+) and acetate ions (Ac.sup.-). The sodium is
considered to be a `spectator` ion--it does not participate in any
equilibria. The acetate (Ac.sup.-) anion undergoes hydrolysis:
Ac.sup.-+H.sub.2OHAc+OH.sup.-
Kb=K.sub.w/K.sub.a=10.sup.-14/1.76.times.10.sup.-6=5.6.times.10.sup.-10
[0091] A buffer is a solution whose composition is designed to
resist changes in pH. Small amounts of acid or base can be added to
a buffer and the pH will change very little. These statements imply
that the buffer solutions are able to react with both H.sup.+ (also
commonly written as H.sub.3O.sup.+) and OH.sup.- ions. Two common
kinds of buffer solutions are ones which contain (1) a weak acid
plus a salt of the weak acid, and (2) a weak base and a salt of the
weak base. A less common type contains a weak acid (e.g., citric
acid) and a salt of another weak acid (e.g., sodium acetate which
is derived from acetic acid).
[0092] For simple aqueous solutions, the buffering action can often
be calculated based on available data, specifically: concentration
of acid, concentration of salts, temperature, and appropriate
equilibrium constants, K. The situation with the acid concentrates
and dialysates of the present invention is more complex. Additional
equilibria are introduced by the addition of calcium (Ca) and
magnesium (Mg) to the dialysate. These metal ions have their own
equilibria with carbonate, acetate, and citrate ions. Equilibrium
constants K, for some of the equilibria are not available and so
their impact on the pH of a dialysate formulation cannot be
absolutely predicted. Direct measurement of solution pH by
titrimetric methods may be used in the formulation of the
dialysate. The predominant equilibria in solution are given by (not
an exhaustive list):
H.sub.3AH.sup.++H.sub.2A.sup.- K.sub.a1=7.10.times.10.sup.-4 at
20.degree. C. (pK.sub.a=3.14)
H.sub.2A.sup.-H.sup.++HA.sup.2- K.sub.a2=1.68.times.10.sup.-6 at
20.degree. C. (pK.sub.a=4.77)
HA.sup.2-H.sup.++A.sup.3- K.sub.a3=6.4.times.10.sup.-6 at
20.degree. C. (pK.sub.a=6.39)
where A represents the citrate anion.
Ac.sup.-+H.sub.2OHAc+OH.sup.-
Kb=K.sub.W/K.sub.a=10.sup.-14/1.76.times.10.sup.-5=5.6.times.10.sup.-10
where Ac represents the acetate anion.
H.sub.2OH.sup.++OH.sup.- K.sub.w=10.sup.-14 at 25.degree. C. (Also
written as 2H.sub.2OH.sub.3O.sup.++OH.sup.-)
HCO.sub.3.sup.-H.sup.++CO.sub.3.sup.-
Ca.sup.2++2Ac.sup.-CaAc.sub.2 K.sub.sp=solubility product constant,
i.e., the solubility of calcium acetate
Mg.sup.2++2Ac.sup.-MgAc.sub.2 K.sub.sp=solubility product constant,
i.e., the solubility of magnesium acetate
3Ca.sup.2++2A.sup.3-Ca.sub.3A.sub.2 K.sub.sp=solubility product
constant, i.e., the solubility of calcium citrate
3Mg.sup.2++2A.sup.3-K.sub.sp=solubility product constant, i.e., the
solubility of Mg.sub.3A.sub.2 magnesium citrate
[0093] Since the A.sup.3- species predominates at a pH above 7.0,
the calcium and magnesium equilibria with lower citrate ions
(HA.sup.2- and H.sub.2A.sup.-) are not considered.
Ca.sup.2++CO.sub.3.sup.2-K.sub.sp=solubility product constant,
i.e., the solubility CaCO.sub.3 of calcium carbonate
Mg.sup.2++CO.sub.3.sup.2-K.sub.sp=solubility product constant,
i.e., the solubility MgCO.sub.3 of magnesium carbonate
[0094] If all of the constants and concentrations were known for
37.degree. C., then the above equations could be set into a matrix
and the pH and buffering action could be obtained by calculation.
The situation is further restrained by the requirement to keep the
pH within a physiological range (especially near the end of
dialysis when the pH of the bicarbonate concentrate tends to rise).
Normally, this could be accomplished with the addition of more
(citric) acid, however, this is precluded by the need to keep the
concentration of citrate ions (from citric acid) as low as
possible. As discussed below, this is required because of the
tendency of calcium and magnesium to combine with citrate ions thus
lowering the serum levels of calcium and magnesium to clinically
unacceptable levels. The solution to this problem is found in
Applicants' selection of the buffer.
[0095] Sodium citrate is not used in the buffer because of the
aforementioned need to maintain an acceptably low total citrate ion
concentration. Acetate or lactate may be used because of (1) their
appropriate buffering action, (2) cost, (3) acetate ions (which are
preferred) are already used (from acetic acid) in dialysate
formulations and thus no new variable is introduced to the
chemistry of the dialysate.
[0096] The buffering action manifests itself by lowering the pH of
the dialysate to physiological, non-alarm levels when the pH of the
bicarbonate is high--either from incorrect mixing or the passage of
time since mixing. When the bicarbonate pH is appropriate, the
buffer is present, but it is transparent to the operation of the
dialysate. When bicarbonate concentrate solutions were used with a
pH of <8.0 the buffering action was not apparent. When
bicarbonate concentrate solutions of 8.1<pH<8.3 were used,
the buffering action was evident (see FIGURE). The buffering action
is particularly evident for sodium acetate concentrations between
0.5 and 3.0 g per liter of acid concentrate, where this is a
preferred range for the acid concentrates of the present
invention.
[0097] In another aspect, the present invention provides
citrate-containing compositions particularly suitable for
peritoneal dialysis (PD). These composition may be in either solid
or liquid form, i.e., either a mixture of dry ingredients, which is
a precursor to the peritoneal dialysate, or a solution of various
solutes, which itself is a peritoneal dialysate. The mixture of dry
ingredients contains, at a minimum, chloride, citrate, bicarbonate
and dextrose, along with one or more cationic species that provide
a neutral (i.e., no net charge) composition. The solution form of
the PD composition contains, at a minimum, water in addition to the
above-listed minimum ingredients required for the dry composition.
Whether in solid or liquid form, the citrate acid-containing
compositions suitable for peritoneal dialysis are sterile.
[0098] The peritoneal dialysate of the present invention (i.e., the
PD solution dialysate) contains water in addition to the following
ingredients, in the indicated amounts, where the amounts are
expressed in terms of mEq per liter of the PD solution: citrate
(0.5-6, preferably 1.5-4.5, more preferably 2-3); chloride (20-200,
preferably 40-150, more preferably 60-120); and bicarbonate (5-100,
preferably 10-70, more preferably 30-40). In addition, the solution
form of the PD composition contains glucose at a concentration, in
terms of g per liter of the solution form, of 10-100, preferably
20-80, more preferably 40-60. In addition, the solution form of the
PD composition contains a sufficient number of
physiologically-acceptable cations to neutralize all of the
citrate, chloride, bicarbonate, and any other anionic species that
may be present in the composition. This PD solution dialysate is
sterile, as required for all dialysates approved for peritoneal
dialysis by the U.S. Food & Drug Administration.
[0099] In a preferred embodiment, the solution form of the PD
composition contains acetate and/or lactate, where in total these
two anions are present in an amount, expressed in terms of mEq per
liter of PD solution, of 0.01-10, preferably 0.1-1, more preferably
0.25-0.75. The cationic species present in the PD solution are
essentially within the same concentration ranges as previously set
forth herein for cationic species (i.e., sodium, magnesium, calcium
and potassium) in the hemodialysis compositions.
[0100] The present invention provides a dry composition which, upon
combination with sterile water, will generate the above-described
PD solution dialysate. This dry composition is, itself, sterile.
According to one approach, such a dry composition can be described
in terms of grams of a specific ingredients per each (one) gram of
citrate. Using these terms, the dry composition contains chloride
in an amount of 5-50, preferably 10-40, more preferably 20-30;
bicarbonate in an amount of 1-50; preferably 5-30, more preferably
10-20; and glucose in an amount of 100-600; preferably 150-500,
more preferably 200-350, where each of these values are grams per 1
gram of citrate. In calculating these amounts, the formula weights
for citrate, chloride, and bicarbonate are 189.1 g/mol, 35.5 g/mol
and 61.0 g/mol, respectively, where each of chloride and
bicarbonate carry a single charge, while citrate carries a triple
charge. The dry PD composition contains sufficient cationic species
to provide a neutral (no net charge) composition. In addition, the
pH of the resulting solution will be within a physiologically
tolerable range, preferably within the range 6.4-7.6.
[0101] According to another approach, the content of the dry PD
composition can be described in terms of the number of
milli-equivalents of a specific charged species present in the
composition per each (one) milli-equivalent of citrate present in
the composition. In these terms, the dry composition contains
chloride in an amount ranging from 1-200, preferably 10-100, more
preferably 30-50 mEq; and bicarbonate in an amount ranging from
1-50, preferably 5-30; more preferably 10-20 mEq. In addition, the
dry PD composition contains glucose in an amount of 100-600;
preferably 150-400, more preferably 200-300, where each of these
values are grams per 1 gram of citrate.
[0102] Both the peritoneal dialysate and the dry precursor thereto
are necessarily sterile in order to be useful in peritoneal
dialysis. Accordingly, the preparation of each is necessarily
conducted under sterile conditions, and/or the resulting
composition is rendered sterile by appropriate sterilizing
treatment. According to one embodiment, the dry PD composition is
prepared by combining sodium chloride (5.67 g), calcium chloride
dihydrate (0.26 g), magnesium chloride hexahydrate (0.10 g) sodium
bicarbonate (2.94 g), anhydrous citric acid (0.15 g), sodium
acetate trihydrate (0.041 g) and dextrose (42.5 g), where each of
the listed chemicals is in sterile form, and the combining
procedure is conducted in a sterile environment. This dry
composition contains 0.15 g citrate, 3.6 g chloride, 2.1 g
bicarbonate and 42.5 g glucose which, in terms of each gram of
citrate, is 24 g chloride, 14 g bicarbonate and 283 g dextrose, and
in terms of each milli-equivalent of citrate is 42 mEq chloride and
14.5 mEq bicarbonate.
[0103] The dry PD composition, and the peritoneal dialysate
prepared therefrom, is described in terms of anionic species
because each anionic species may be introduced into the composition
in any dry form that is physiologically acceptable and contains the
anionic species of interest. Thus, for example, "citrate" can be
introduced into the dry composition in any dry form that contains
citrate. Examples are citric acid (anhydrous), citric acid
monohydrate, trisodium citrate, citric acid disodium salt
sesquihydrate, citric acid monosodium salt, citric acid
tripotassium salt monohydrate, etc. Likewise, each of the
bicarbonate and chloride may be introduced simultaneous with
cations selected from sodium, potassium, magnesium and calcium, and
may be in anhydrous or hydrate forms. Accordingly, the dry
composition is described in terms of "chloride", "citrate", and
"bicarbonate", rather than specifying any particular salt or
protonated form thereof.
[0104] The chloride is present in the dry composition in the form
of a salt. Suitable chloride salts include, without limitation,
sodium chloride, potassium chloride, calcium chloride, and
magnesium chloride. A preferred chloride salt is sodium
chloride.
[0105] The citrate is present in the dry composition in form of an
acid and/or a salt. Citric acid is a suitable acid form of citrate.
Trisodium citrate, tripotassium citrate, and calcium citrate (i.e.,
tricalcium dicitrate) are all suitable salt forms of citrate. The
citrate may be in a mixed acid/salt form, i.e., complexed
simultaneously to one or more protons and one or more metal
cations. Typical examples of citrate in mixed acid/salt form
include, without limitation, potassium dihydrogen citrate,
dipotassium hydrogen citrate, and disodium hydrogen citrate. A
preferred citrate is citric acid.
[0106] The bicarbonate is present in the dry composition in the
form of a salt. Suitable bicarbonate salts include, without
limitation, sodium bicarbonate, and potassium bicarbonate. A
preferred bicarbonate salt is sodium bicarbonate.
[0107] Glucose is a component of most of the currently used
peritoneal dialysates, and is incorporated into the peritoneal
dialysate (and precursor thereto) of the present invention in order
to provide the benefits that glucose is known to provide to
peritoneal dialysates. For example, glucose is primarily useful as
an osmotic agent, as discussed previously, and is also recognized
to mitigate some of the undesirable side-effects of peritoneal
dialysis. The glucose may also provide some nutritional supplement
to the subject undergoing to the dialysis treatment. The most
typical glucose isomer currently used in peritoneal dialysate is
dextrose, i.e., .alpha.-D-glucose. This is a commonly known
material of commerce, and is available in both hydrated and
anhydrous forms. Either form may be used in the present PD
composition.
[0108] Although the dry composition will be dry to the touch, it
may contain some water. For instance, several of the salts and
acids mentioned above as suitable ingredients for the dry PD
composition are commonly available in hydrated form. Such hydrated
forms are suitably used in preparing the dry PD composition
provided herein. Each of the above-mentioned ingredients of the dry
PD composition is available from many commercial supply houses.
See, e.g., Sigma-Aldrich (http://www.sial.com). Preferably, the
ingredients are of United States Pharmacopeia (USP)-grade purity or
higher, which is generally recognized as a purity of at least about
95%.
[0109] Optional ingredients may be present in the dry PD
composition. Suitable optional ingredients include, without
limitation, amino acids.
[0110] The dry PD composition is readily prepared simply by mixing
together weighed quantities of the various dry sterile ingredients
under sterile conditions. Mixing is readily accomplished by
agitating a combination of the ingredients until a homogeneous
mixture results. The pre-weighed dry mixture may be packaged in
hermetically-sealed packages for convenience in shipping, and to
allow a technician to more easily prepare a solution form of the
dry composition.
[0111] The dry dialysate powder technology of the present invention
allows the preparation of peritoneal dialysate. This aspect of the
invention creates a unique peritoneal dialysate using, in a
preferred embodiment, citric acid as the acidifier, dextrose at
concentrations exceeding 2.0% and bicarbonate as the basic anion.
Other ingredients would include water as well as chloride, sodium,
potassium, magnesium, and calcium, which could all be included at
the concentration ranges specified for hemodialysis dialysate.
Peritoneal dialysate would require no precursor (other than the dry
powder) since the volumes of dialysate used per treatment are just
a small fraction of the amounts used in hemodialysis. Making the
peritoneal dialysate just prior to use (i.e., by adding sterile
water to the sterile dry PD powder) would allow the use of
bicarbonate as the basic anion. Normally, bicarbonate cannot be
used in PD because solutions of it with citric acid do not have
sufficient long-term stability to permit storage. To overcome this
stability problem, currently used PD compositions typically contain
lactate (rather than bicarbonate) as the basic anion. However, some
health care professions prefer bicarbonate as the basic anion, and
the present invention addresses that need.
[0112] The precise order in which the sterile water and dry
ingredients are combined is unimportant. As one option, sterile
water may be added to the dry PD composition described above. As
another option, a desired volume of sterile water may be provided,
and to this may be added each of the various other (sterile)
ingredients of the solution PD composition. Typically, the final
solution should be stirred or otherwise agitated, e.g., shaken, to
form a homogeneous composition. "Handbook of Dialysis" 2.sup.nd Ed.
Daugirdas, J. T. and Ing T. S., eds. (Little, Brown, Boston, 1994)
provides an extensive discussion of peritoneal dialysis (as well as
hemodialysis).
Physiological Effects
[0113] Citric acid was identified as a potential acidifying agent
for dialysate because it is an inexpensive physiological acid. In
addition, it has an extensive history of use in blood banks and
also has been successfully used for regional anticoagulation in
hemodialysis. Both these prior uses are based on the calcium
binding effect of the citric acid. It is empirically observed that
blood will coagulate if the concentration of free calcium in the
blood is above a certain critical concentration. As citric acid is
added to blood, the citrate binds with the free calcium and reduces
its concentration. When the free calcium concentration is reduced
to a certain point, the blood will no longer coagulate.
[0114] In the present invention, citric acid is employed in
dialysate as an acidifying agent to reduce the pH of the dialysate.
However, using more than about 2.4 mEq/L of citric acid in
dialysate may possibly cause a decrease in serum calcium
concentration, which may be clinically undesirable. At the level of
2.4 mEq/L of citric acid in dialysate, the increase in blood
citrate concentration is typically small enough to not cause any
noticeable detrimental effect on the coagulation behavior of blood.
Indeed, there is typically no measurable increase in a patient's
clotting time beyond that already achieved with their normal
anticoagulation medicine, heparin.
[0115] Generally, kidney failure patients suffer from chronic
acidosis. Their kidneys cannot rid the body of the H+ ions produced
during normal metabolism. As a consequence, their bodies use
excessive amounts of bicarbonate to buffer excess H+ ions. Because
of the constant use of bicarbonate to neutralize acid, these
patients have lower than normal levels of bicarbonate (carbon
dioxide) when they arrive for their dialysis treatment.
Traditionally, dialysis treatment seeks to correct an acidosis
problem by using dialysate that contains higher than normal serum
concentrations of bicarbonate. Thus, during treatment, the blood
bicarbonate increases because of diffusion of some of this excess
bicarbonate into the blood which helps restore total body
bicarbonate. However, the traditional dialysis with a dialysate
bicarbonate concentration of about 37 mEq/L is often not enough to
maintain normal blood bicarbonate between dialysis sessions.
Consequently, by the time the patient comes for the next dialysis
session, the blood bicarbonate is again subnormal. The buffered
citrate dialysate(s) of the present invention have shown some
effect at replenishing the body's bicarbonate levels, thus helping
to treat chronic acidosis.
[0116] The following examples are provided for purposes of
illustration, not limitation.
EXAMPLES
Example 1
Acid Concentrate Formulation
[0117] The following amounts of the indicated USP-grade chemicals
were carefully weighed out: 262.0 g sodium chloride (FW 58.45),
9.70 g calcium chloride (dihydrate, FW 147.02), 3.40 g magnesium
chloride (hexahydrate, FW 203.3), 90.0 g dextrose (FW 180.16), 7.0
g citric acid (anhydrous, FW 192.12) and 1.75 g of sodium acetate
(trihydrate, FW 136.08). The chemicals were placed in a large
calibrated beaker and AAMI quality water was added to the 900 ml
mark. The beaker was placed on a stirring plate and a stirring bar
was used to agitated the chemicals and water. After approximately
10 minutes of stirring, the chemicals had completely dissolved and
the solution was `crystal clear.` The stirring bar was removed and
the solution was `topped off` with additional AAMI quality water to
the 1 liter mark on the beaker. The stirring bar was reintroduced
and the solution was stirred for another 3 minutes.
Example 2
Hemodialysis
[0118] The beaker of solution as prepared in Example 1 was taken to
a Fresenius hemodialysis machine that was ready for use in testing
(bypass) mode. In this configuration the machine makes dialysate in
the same manner as when a patient is undergoing a dialysis
treatment. The treated water supply line was attached to the
machine and a container of bicarbonate concentrate was carefully
prepared. All solutions were then attached to the machine and it
was turned on.
[0119] The machine was allowed to run for 10 minutes at a dialysate
flow rate of 800 ml/min. to ensure the prepared solutions had
thoroughly filled their appropriate pathways through the machine.
Additionally, both the machine's conductivity meter as well as an
additional conductivity monitor that had been attached to the
dialysate outflow line were monitored, with readings found to stay
within the acceptable range (between 1310 and 1330 millisiemens).
The pH of the machine-mixed dialysate was monitored by sampling the
drain tube outflow at several intervals which averaged 10 minutes
apart. The pH was 7.4, which was within the target range of 7.3 to
7.5. A sample of the outflow was analyzed at the University of
Washington Medical Center's laboratory to confirm that the
concentrations in the final dialysate were all within acceptable
ranges for hemodialysis.
[0120] Finally, after receiving the appropriate approvals, the
dialysate precursor and the resulting dialysate produced by the
hemodialysis machine were repeatedly tested in actual patient
treatments during clinical trials of the new dialysate. Throughout
the trials, even with dialysis sessions lasting up to five hours,
there were no instances of pH alarms noted.
Example 3
Dialysate Composition
[0121] One liter of dialysate composition, excluding sodium
bicarbonate, in mEq/L, contains: sodium, 100.3; chloride, 104.25;
calcium, 2.5; potassium, 1.0; magnesium, 0.75; acetate, 0.3; citric
acid, 2.4; and, in g/I, dextrose, 2.0. The total chemical
composition of this dialysate composition (which did not contain
sodium bicarbonate) was (in grams): NaCl (5.822); CaCl.sub.2 2
H.sub.20 (0.139); KCl (0.074); MgCl.sub.2 6 H.sub.2O (0.036);
NaC.sub.2H.sub.3O.sub.2 (0.039); C.sub.6H.sub.8O.sub.7 (0.155) and
C.sub.6H.sub.12O.sub.6 H.sub.2O (2).
[0122] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *
References